The inactivation of tumor suppressor genes or the activation of oncogenes have been revealed as underlying causes for many tumors. The challenge is now to define their presumed roles in normal growth regulation, and to determine how their deregulation leads to tumor formation. It is the focus of this project to elucidate the function of one such tumor suppressor gene, NF2. Germline deletions in NF2 cause Neurofibromatosis II, a disease predisposing for certain nervous system tumors. These tumors have lost/inactivated the NF2 protein due to a further mutation in the second NF2 allele. Moreover, the inactivation of NF2 is also seen in sporadic brain tumors. NF2 is structurally related to the ezrin/radixin/moesin (ERM) family of membrane-cytoskeleton linker proteins. This relation places NF2 into a new class of cytoskeletal tumor suppressors. The hypothesis to be tested is whether cytoskeletal proteins like NF2 and the ERM family are involved in growth inhibiting pathways, either directly or indirectly by chanelling these signals from the membrane to the nucleus. To this end, we have cloned the homologs of NF2 and the ERM family in C. elegans, hoping to take advantage of the genetic power of this invertebrate system. In C. elegans it will be possible (1) to observe the impact of these proteins on normal growth and development, (2) to genetically manipulate these proteins in vivo and observe the effects in the living organism and (3) to determine pathways using genetic screens discovering interacting partners. The preliminary results on this project have been obtained by the candidate at the MGH Cancer Center directed by Dr. K. Isselbacher (Sponsor). This environment is dedicated to the investigation of tumor suppressor genes, oncOgenes, cell signalling and the cell cycle; and further dedicated to use invertebrate genetics for this purpose. Dr. F. Solomon, MIT, as an expert on cytoskeletal proteins, has been involved in the designing phase of this project and, as a ce-Sponsor, will have dominant scientific impact on its further development. The C. elegans expertise is provided by the candidate's coworker Dr. J. Fleming and by Dr. Horvitz who will serve as a consultant. The candidate is a Pediatric Oncologist with completed clinical training plus research training, with a major interest in basic research. Dr. Medearis, Chief of the Department of Pediatrics at MGH, concurs in the candidate's wish to maintain her clinical work on a restricted schedule in order to support her future development with the longer term perspective of an academic career in Pediatric Oncology. This award will allow the candidate to receive additional training in the areas of cytoskeletal proteins and C. elegans, which will be indispensable for the proposed project and which will expand the candidate's current understanding of oncogenesis. With this further period of training the candidate is expected to assume the role of an independent investigator with her own research program.